The HIV pandemic derives from zoonotic transmission of SIV from African monkeys. Sooty Mangabeys (SM) are natural hosts of SIV and, in contrast to HIV infection in humans or SIV infection in non-natural hosts such as Rhesus Macaques (RM), do not develop CD4 T cell loss or progress to AIDS. Studying the immune response in SIV infected SM could provide insights into the mechanisms of AIDS pathogenesis in humans and may lead to the development of new therapies for HIV infection. We propose to perform experiments aimed at answering three fundamental but still unanswered questions on the immunopathogenesis of SIV infection in SMs: (1) What are the turnover rates (i.e., cell proliferation and death) of CD4+ T lymphocytes and the lifespan of SIV-infected cells? (2) What goes wrong in the subset of SIV-infected SM that loses CD4+ T cells overtime? (3) What is the role of SIV-specific, cellular immune responses in disease- resistance? We believe that the results of these studies may help understand the immunopathogenesis of HIV infection in humans. These conceptual advances may eventually translate into new, immuno-based therapeutic approaches and thus improve the clinical management of HIV-infected patients. [unreadable] [unreadable] [unreadable]